DESCRIPTION: (Applicant's Abstract) Cocaine continues to be one of the most commonly abused and problematic psychoactive substances in the US. Chronic cocaine use results in a range of cognitive and behavioral changes. Neuropsychological studies suggest significant impairment in learning and memory, visuospatial skills, calculations, and abstraction. Cocaine is now known to produce a withdrawal syndrome unique among drugs of abuse. Despite these clinical observations, the question of whether cocaine is neurotoxic to the human brain has not been established. Little research has been done regarding cocaine neurotoxicity in the human brain, not only because of the complexity of the question, but also due to the lack of non-invasive in vivo methods to repeatedly detect neurochemical changes and neuronal loss in the human brain. The long term goal of this project is to develop and apply non-invasive magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (FMR) methods to characterize the physiological and neurochemical alterations in the human brain following acute cocaine administration and to determine the mechanisms, reversibility, and neurotoxic susceptibility of neuronal tissue to these neurochemical alterations. As such, the following specific aims will be addressed: 1) Apply lH chemical shift imaging (CSI) technology at 0.5 T for the detection of Glu and NAA in human brain, 2) Determine the regional cerebral activation patterns within the human CNS using phase-encoded echo-planar image (PE-EPI) mapping during acute cocaine dose-response and time-course regimens, 3) Determine regional neurochemical alterations within the human CNS following acute cocaine administration by employing lH CSI technology at 0.5 T to map Glu and NAA and proton-decoupled 31p 2D-CSI at 1.5 T to measure ATP, Pi, phosphocreatine (PCr) and tissue pH, 4) Determine the reversibility of the above neurochemical effects and putative cocaine-induced neurotoxicity within the human CNS through the detection of Glu, NAA, and 31p parameters during withdrawal from chronic cocaine use, 5) Determine the ability and pattern of responsivity of the brain while subjects perform cognitive tasks known to involve frontal lobe regions (e.g., working memory, Stroop Interference, Levine) in individuals undergoing withdrawal from chronic cocaine use.